Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors. It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (μ), delta (δ) and kappa (κ), have distinct pharmacological profiles, anatomical distributions and functions. See, for example: Wood, P. L., Neuropharmacology, 21, 487-497, 1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al., J. Recept. Res., 12, 267-286, 1992; and Mansour et al., Opioid I, ed. Herz, A. (Springer, Berlin), 79-106, 1993. The δ receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The μ receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects. The κ receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, tussis, gut motility, temperature control and various endocrine functions. They also produce analgesia. See, for example: Leander et al., J. Pharmacol. Exp. Ther., 234, 463-469, 1985; Morley et al., Peptides 4, 797-800, 1983; Manzanares et al., Neuroendocrinology, 52, 200-205, 1990; and Iyengar et al., J. Pharmacol. Exp. Ther, 238, 429-436, 1986; U.S. Pat. No. 6,177,438.
Most clinically used opioid analgesics, such as morphine and codeine, act as μ receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence-forming side effects. Compounds that are κ-receptor agonists act as analgesics through interaction with κ opioid receptors. The advantage of these agonists over the classical μ receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
A large number of classes of compounds which act as agonists at κ opioid receptors have been described in the art including the following illustrative classes of compounds:                U.S. Pat. No. 4,065,573 discloses 4-amino-4-phenylcyclohexane ketal compounds allegedly having analgesic activity.        U.S. Pat. No. 4,145,435 discloses N-(2-amino-cycloaliphatic)-phenylacetamide compounds allegedly having analgesic activity and narcotic antagonist activity.        U.S. Pat. No. 4,098,904 discloses N-(2-amino-cycloaliphatic)-benzoamides and naphthamides allegedly useful for relieving pain.        U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives allegedly having analgesic properties and reduced physical dependence liability properties, relative to morphine and methadone.        U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides allegedly useful as analgesics and having low abuse liability.        U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and thia-spirocyclic compounds allegedly having analgesic activity, low physical dependence and abuse liability properties and little dysphoric inducing properties.        U.S. Pat. No. 4,663,343 discloses substituted naphthalenyloxy-1,2-diaminocyclohexyl amides allegedly useful as analgesics.        U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides allegedly having high κ-opioid affinity, selectivity and potency and allegedly useful as analgesics, diuretics, anti-inflammatory and psychotherapeutic agents.        U.S. Pat. No. 5,532,266 discloses arylacetamides allegedly having high κ-opioid affinity useful as pharmaceutical agents for providing an analgesic effect and/or neuroprotective effect.        U.S. Pat. No. 5,688,955 discloses substituted piperidines, substituted naphthalenes, aryl-substituted amides, and cyclohexyl-substituted amides having κ opioid agonist activity, compositions containing them and methods of using them as analgesics.        U.S. Pat. No. 5,804,595 discloses amino acid conjugates of substituted 2-phenyl-N-[1-(phenyl)-2-(1-heterocycloalkyl- or heterocycloaryl-)ethyl]acetamides allegedly useful for selectively agonizing κ opioid receptors in mammalian tissue.Although numerous compounds have been reported to be potent and selective κ opioid agonists, many of these compounds were found in our assays to be very potent inhibitors of a number of human cytochrome P450 enzymes, particularly CYP2D6, CYP2C9 and CYP3A4.        
Cytochrome P450 enzymes are heme-containing membrane proteins localized in the smooth endoplasmic reticulum of numerous tissues, including, in particular, the liver. This family of enzymes catalyzes a wide variety of oxidative and reductive reactions and has activity towards a chemically diverse group of substrates. Oxidative biotransformations catalyzed by cytochrome P450 monooxygenases include aromatic and side chain hydroxylation, N-, O-, and S-dealkylation, N- and S-oxidation, N-hydroxylation, deamination, dehalogenation, and desulfuration. These enzymes are the major catalysts of drug biotransformation reactions and also serve an important detoxification role in the body. The cytochrome P450 enzymes catalyze oxidative reactions of toxins in the body by making them more water-soluble.
Because some of these κ agonist compounds are potent inhibitors of cytochrome P450 enzymes, they interfere with the body's ability to detoxify. For example, lethal clinical consequences can result from CYP3A4 inhibitors with drugs that are metabolized by this enzyme. As a further example, the use of an inhibitor of cytochrome P450 could render a normally safe and effective dose of a drug that is metabolized by cytochrome P450 toxic because the enzyme does not reduce the level of the drug in the patient to safe levels. In this way, the inhibition of cytochrome P450 enzymes could preclude clinical development of a given compound. For further discussion on drug interactions, see, for example, the Guidance for Industry: In Vivo Drug Metabolism/Drug Interaction Studies—Study Design, Data Analysis, and Recommendations for Dosing and Labeling prepared by the Food and Drug Administration (November 1999), the disclosure of which is incorporated herein by reference.
Thus, there is still an unfulfilled need for compounds with κ opioid receptor activity that may be used in methods to provide beneficial pharmaceutical characteristics while minimizing undesirable side effects generally associated with administering these exogenous opioids, particularly inhibition of cytochrome P450 enzymes. The present invention is directed to these, as well as other important ends.